Description
Artemisia annua L. is a common type of wormwood that belongs to the family of the Asteraceae. It is native to temperate Asia but naturalized throughout the world.
Artemisinin is an ingredient of A. annua. Artemesin and its semi-synthetic artemisinin derivatives (including dihydroartemisinin, artesunate, artemether and arteether) are used for the production of combination therapies for treatment of malaria (ACTs = Artemisinin-based Combination Therapy).
Efficacy
Animal studies suggested that artemisinin and related compounds inhibit tumour growth and metastasis. However, there is no evidence from clinical trials at the moment that the anticancer effects from animal studies translate into benefits for cancer patients. No clinical trials of A. annua and only two randomised clinical trial of artesunate are available.
In summary, there is insufficient evidence from two randomized clinical trials to make any statements regarding the efficacy of Artesunate as an antitumor agent for any cancer.
Safety
Experiences from malaria treatment indicate a good tolerability of artemisinin-based drugs. In clinical studies, oral artemisinin and artesunate have been shown to be safe with no serious adverse effects. Artemisinin and its derivates influence the activity of cytochrome P450 Cyp3A4, CYP2C9, CYP1A2 and CYP2D6, although the clinical significance is unclear.
Description and background
Artemisia annua, also known as sweet wormwood, sweet annie, sweet sagewort and annual wormwood (Chinese: qīnghāo), is a common type of wormwood that is native to temperate Asia but naturalized throughout the world (Bhakuni 2001). It belongs to the family of Asteraceae and has fern-like leaves, bright yellow flowers and a camphor-like scent. Glandular structures (trichomes) producing a wide range of bioactive compounds (mostly terpenoids) can be found on the surface of leaves, stems and flowers.
Note: Not to be confused with Artemisia absinthium (absinthe, wormwood).
Artemisia annua was used by Chinese herbalists in ancient times to treat specific fevers, but had fallen out of common use until it was rediscovered in 1970 when the Chinese Handbook of Prescriptions for Emergency Treatments (340 AD) was recovered. This ancient pharmacopeia contained a recipe for a tea from the dried leaves of A. annua to be used in case of specific fevers. In 2010 it was discovered that A. annua has already been cited in the earliest Chinese medical prescriptions, the Mawagndui tomb texts dating back to 168 B.C. There, it is prescribed for female haemorrhoids and as a sexual tonic, being mixed with other herbs, including cinnamon and ginger, and administered in boiled urine (McGovern 2020). In 1971, scientists demonstrated that the plant extracts had antimalarial properties in primate models (van Agtmael 1999).
After its recommendation as an antimalarial drug by the WHO in 2006 (WHO 2006), extensive research was conducted about its mechanism of action. Among activities against other parasites and against viruses, anti-cancer properties of artemisinin lead to its investigation in oncology. (Li 2010).
There are no data available on the prevalence of use of A. annua in the treatment of cancer.
Ingredients
The phytochemical composition of A. annua has been reviewed in great detail by Bhakuni et al 2001: The most relevant compounds are sesquiterpenoids (ex. artemisinin), triterpenoids, flavonoids (polymethoxylated flavonoids), chromenes and essential oil components. (Bhakuni 2001) The content of an A. annua extract depends on the solvent used for extraction. Aqueous extracts seem to contain less polymethoxylated flavonoids than alcohol extracts, but they do contain a high amount of mono-caffeoyl- and mono-feruloyl-quinic acids, di-caffeoyl- and di-feruloyl-quinic acids. Alcoholic extracts seem to contain the highest antioxidant potential. Also the flavonoids casticin and artemetin that have shown synergism with artemisinin against malaria are less extracted in aqueous extracts (Carbonara 2012; Iqbal 2012; Weathers 2012).
Besides A. annua itself, this summary also reviews current literature on artesunate, dihydroartemisinin and artemether, which are semi-synthetic derivatives of artemisinin. Far more research has been published on the effect of these compounds than on artemisinin itself. Arteether, another semisynthetic derivative that has been used in antimalarial treatment has not been the focus of anticancer research to date.
Application and dosage
There is no documented safe or effective dose for the possible use of A. annua derived products for the treatment of cancer in adults or children. The Chinese pharmacopoeia lists the dry herb as a remedy for fever and malaria. The daily dose described is 4.5 to 9 grams of dried herb to be prepared as a tea infusion with boiling water. The artemisinin content varies from 0.02% to 1.1% of the dry weight6. In addition, artemisinin and its semisynthetic derivatives are used in antimalarial treatment in artemisinin-based combination therapies, with daily doses between 100 and 200mg (WHO 2006).
In a dose-finding study of intravenous artesunate, the maximum tolerated dose was 18mg/kg body weight per week. (Deeken 2018) However, higher grade adverse effects such as neutropenic fever or allergic reactions (CTCAE grade 3) were already evident at 12mg/kg in the study. Other adverse reactions at higher doses included diarrhoea, vomiting, hepatitis, and dizziness, some of which were also severe (CTCAE grade 4).
Mechanism of anti-cancer action
Artemisinin, the natural endoperoxide of A. annua, and its semisynthetic derivates dihydroartemisinin, arthemether, artheether and artesunate are considered to be the primary active constituents for antimalarial and anti-cancer activity (Firestone 2009; Efferth 2006). Also the polymethoxyflavonoids are indicated as important compounds with potential anticancer activity. Cancer cell lines show a differential sensitivity as well as resistance to this group of compounds. Different genes which influence the sensitivity or the resistance to treatment have been identified. These genes could potentially function as markers indicating the expected efficacy of a clinical therapy (Li 2008; Huang 2007). In contrast to popular belief that the cytotoxic activities would only be due to the non-specific generation of reactive oxygen species, it has become clear that artemisinin-related endoperoxides additionally have various specific molecular targets and can significantly influence the expression of key regulatory proteins of the cell cycle (Firestone 2009; Efferth 2006; Huang 2007, Li 2007). Artemisinin-related endoperoxides were found to significantly inhibit angiogenesis and also to induce apoptosis (Firestone 2009; Chen 2004). Iron plays a crucial role in the cytotoxic activities of artemisinin-related endoperoxides through the generation of both ROS and carbon-centred radicals. In general, the addition of iron has been shown to enhance both the cytotoxicity and selectivity of the treatment, but not in all cell lines (Firestone 2009; Chen 2004).
AMDT is a sesquiterpene found in the hairy roots of A. annua. It has been demonstrated that it induces apoptosis through the mitochondrial dependent pathway in human lung 95-D cells. Cytotoxicity of this compound was also found in ovary, liver, and cervix cancer cells (Zhai 2010).
No cross-resistance has been found between the artemisinin-related as well as the unrelated compounds, so cells resistant to one compound retain sensitivity to another one (Efferth 2011).
Animal studies suggest that artemisinin and related compounds inhibit tumour growth and metastasis and prolong survival upon administration of 10-100mg/(kg day) in xenografts of a wide variety of cancer cells (Bhakuni 2001; NMD 2021; Firestone 2009; MSKCC 2021). The dosages applied are much higher than those used in anti-malaria treatment. Intermittent higher dosage therapy appears to be more efficient than daily dosing.
Alleged indications
Apart from malaria, A. annua is also used in cases of fever, headaches, infections and inflammations (MSKCC 2021). It has been claimed to kill cancer cells and to be especially effective in breast cancer and leukaemia (Singh 2001; Singh 2005).
Legal issues
There are no A. annua derived drugs that are approved for cancer treatment.
While there are no clinical trials with A. annua preparations available, two randomised clinical trials (RCTs) with the semisynthetic derivative artesunate in cancer treatment have been published (Zhang 2008; Krishna 2014).
Description of studies
Anticancer treatment
In the open label 2-arm study, at least 2 cycles of chemotherapy (vinorelbine/cisplatin) were applied with or without artesunate in 120 Chinese patients with unresectable non-small lung cancer. (Zhang 2008) The authors found no significant differences between the groups in mean survival time, 1-year survival rate and quality of life. However, the artesunate group had a significant higher disease control rate (88,2% vs. 72,7% [complete + partial response + stable disease]) and a significant longer time to progression (24 vs 20 weeks). As there was an imbalance in the disease stages between the groups (more stage IV diseases in the control group) and an unblinded outcome assessment, the risk of bias in this study is high.
In a placebo-controlled double-blinded study, Krishna et al (Krishna 2014) examined the effect of preoperative Artesunate on the tissue apoptosis rate after surgery in 20 patients (9 Artesunate, 11 placebo) with colorectal carcinoma who were scheduled for curative resection. Patients received 200mg Artesunate for 14 days up to 48-72h before planned surgery. The authors reported an unexpected high apoptosis rate in both groups and no difference between the groups. During the follow-up of a mean of 42 months, there were six recurrences in the placebo group and one recurrence in the Artesunate group. The control group had a slightly higher tumour stage (Duke classification) at baseline.
There are two case reports published with artesunate, both reporting stabilization or regression of tumour growth during treatment with additional artesunate, while the tumour was progressing under standard treatment alone Singh 2002; Berger 2005). In a third report of a patient who received artemether, a reduction in density of the tumour and improved quality of life was observed (Singh 2006).
Adverse events
Artemisinin
Artemisinin derived drugs are available for the treatment of malaria. Except for two case reports, no major side effects have been reported in humans at doses used for the treatment of malaria but it is still unknown whether the higher doses that could be required for the treatment of cancer patients could cause major side effects.
It has been reported that the oral intake of A. annua may cause abdominal pain, bradycardia (abnormally slow heartbeat), diarrhoea, nausea, vomiting, decreased appetite, flu-like symptoms, fever, and decreased reticulocyte count (MSKCC 2021)
In a placebo-controlled study, oral intake of Artemisia extracts up to 300-600mg/day for 12 weeks in 14 patients with osteoarthritis of the hip and knee (Stebbings 2015) did not reveal any serious adverse effects according to CTCAE that were labeled “associated” with the therapy. Moderate adverse effects occurred almost exclusively at high doses (600mg/day) with gastrointestinal discomfort, as well as elevation of transaminases, back pain, and vomiting.
Topical application of A. annua may cause dermatitis (NMD 2021).
Artesunate
In a prospective uncontrolled trial of oral artesunate intake up to 200mg daily for 1-37 months in metastatic breast cancer patients, no serious adverse effects were observed according to the authors (von Hagens 2017) The adverse effects that occurred were blood count changes, dizziness and fatigue.
Hearing loss is another known side effect artesunate. A prospective phase 1 clinical trial in 23 breast cancer patients receiving 100-200mg oral artesunate for 4 weeks showed no dose-limiting audiotoxicity (Koenig 2016)
The authors of a phase 1 trial (Deeken 2018) of intravenous artesunate in 19 patients with advanced solid tumors determined the maximum tolerated dose was 18mg/kg body weight per week. However, higher grade adverse effects such as neutropenic fever or allergic reactions (CTCAE grade 3) were already evident at 12mg/kg in the study. Other adverse reactions at higher doses included diarrhea, vomiting, hepatitis, and dizziness, some of which were also severe (CTCAE grade 4)
Interactions
Preclinical studies had suggested that artemisinin and its derivates could influence the activity of the cytochrome P450 enzymes CYP3A4 and CYP2C19.
One clinical study (Svensson 1998) on 9 healthy volunteers had found no effect of artemisinin on cytochrome p450 3A4 activity, an induction of CYP2C19 activity. Another clinical study (Asimus 2007) with 75 healthy volunteers, divided into 5 groups receiving different derivates of artemisinin, suggested the influence of artemisinin and its derivates on the activity of several cytochrome P450 enzymes, with unclear clinical significance. In this, artemisinin, artemether and dihydroartemisinin (from the prodrug artesunate) induced CYP3A4, artemisinin and arteether induced CYP2C19, artemisinin, dihydroartemisinin and arteether inhibited CYP1A2. There was a two-stage effect on CYP2D6 with an inhibition on day one and an induction on day 5 for the artemisinin and dihydroartemisinin group. The authors conclude, that “the magnitudes of the mean changes were generally low and are not expected to present a problem in the general patient population”
Contraindications
Known serious hypersensitivity (eg, anaphylaxis) (FDA 2020).
The first trimester of pregnancy is a relative contraindication due to potential teratogenic effects, although its safety was shown in clinical studies (Moore 2016).
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Citation
Behzad A, CAM Cancer Collaboration. Artemisia annua [online document], Jun 30, 2022.
Document history
Latest update: June 2022
Next update due: June 2025
